Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response

Abstract

Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 (IL-6) superfamily, has recently been shown to induce several inflammatory responses when administered to healthy animals, including induction of fever and a hepatic acute phase protein response. In the present report, 250 micrograms.kg body wt-1.day-1 of recombinant rat CNTF or murine IL-6 were repeatedly administered to healthy mice over a 7-day period in an effort to compare biological responses. In addition to its in vivo capacity to elicit a hepatic acute phase response, administration of CNTF, but not IL-6, produced profound anorexia and lean tissue wasting in mice. In C57B1/6 mice, 7 days of CNTF administration led to a 21% loss in carcass protein content, resulting from carcass protein breakdown rates being increased 218% over freely fed controls (both P < 0.01). Protein synthesis rates in carcass protein were also increased in CNTF-treated mice compared with both freely fed animals and mice pair-fed equivalent quantities of food. In contrast, administration of equivalent quantities of murine IL-6 had no effect on food intake or body weight in mice, although IL-6 produced a similar hepatic acute phase response, as determined by increases in serum amyloid P and seromucoid fraction and increases in total hepatic protein synthesis. However, when CNTF was coincubated with extensor digitorum longus muscles from juvenile rats in vitro, rates of total muscle and myofibrillar protein degradation and muscle protein synthesis were unchanged. We conclude that CNTF can regulate in vivo both skeletal muscle remodeling as well as the distant anorexia and hepatic acute phase protein responses. In the case of skeletal muscle, these actions are both indirect and independent of the associated anorexia. These properties of CNTF are distinct from IL-6, which when administered to the mouse at these doses is neither anorexigenic nor cachexia producing.

Mechanisms of Cancer Cachexia

“…However, further studies with this tumor suggested that IL-6 alone could not be responsible for production of cachexia, since serum levels of IL-6 were raised equally in mice bearing clones of the colon-26 tumor, which were and were not capable of inducing cachexia (245). As with TNF-␣, IL-1 can induce body weight loss and anorexia in mice (184), but IL-6 was found to have no effect on food intake or body weight, although it produced an hepatic APR (68). However, another member of the IL-6 superfamily ciliary neurotrophic factor (CNTF) produced profound anorexia and tissue wasting when administered at the same dose level as IL-6.…”

“…However, other studies have been unable to induce a wasting effect by recombinant IL-6 in mice, even with repeated administration (68). A recent study (14) used the Apc Min/ϩ mouse, an established model of colorectal cancer and cachexia, to determine the role of circulating IL-6 and polyp burden for the development of cachexia.…”

Proinflammatory cytokines, nutritional support, and the cachexia syndrome

“…30,31 receptor that then complexes with gp 130. By sharing a single signal transduction pathway, all these memIn general, although the protein response to inflammation, regardless of its source, is one of inbers of the IL-6 super family share with IL-6 the ability to induce an acute phase response ( inflammation often elicits a cytokine cascade in which a Summarized from Moldawer et al, 40 Espat et al, 47 Moldawer et al, 77 and unpublished data of Moldawer et al…”

“…47 Doses as low as 25 mg/kg body weight of CNTF administered members of the IL-8 family, KC/GRO). 53,54 Under such conditions, it is difficult to resolve the contribution subcutaneously in the mouse can produce an increase in serum amyloid A, P, and a 1 -acid glycoprotein conthat each of these mediators is playing in the acute phase response.…”

Proinflammatory cytokines, nutritional support, and the cachexia syndrome

“…IL-6, CNTF, LIF, IL-11 and oncostatin-M all Total hepatic protein and hepatic secretory acute phase protein synthesis are also increased in cancer share in common signal transduction via the glycoprotein (gp) 130 complex. [44][45][46][47][48] They differ among themand acute inflammation, whereas total secretory protein synthesis remains constant or is increased. 28 Albuselves in the ligand-binding protein, but the ligand receptor complex subsequently interacts with a commin synthesis declines in patients with cancer, 29 infections, and sepsis, but this decline is offset to a large mon gp 130 to transduce the signal.…”